tbuckley/cabot-search huggingface dataset:
New Insights into the Structure and Function of Class B1 GPCRs
Authors: Brian P Cary, Xin Zhang, Jianjun Cao, Rachel M Johnson, Sarah J Piper, Elliot J Gerrard, Denise Wootten, Patrick M Sexton
Journal: Endocrine Reviews (2022)

Abstract G protein–coupled receptors (GPCRs) are the largest family of cell surface receptors. Class B1 GPCRs constitute a subfamily of 15 receptors that characteristically contain large extracellular domains (ECDs) and respond to long polypeptide hormones. Class B1 GPCRs are critical regulators of homeostasis, and, as such, many are important drug targets. While most transmembrane proteins, including GPCRs, are recalcitrant to crystallization, recent advances in cryo-electron microscopy (cryo-EM) have facilitated a rapid expansion of the structural understanding of membrane proteins. As a testament to this success, structures for all the class B1 receptors bound to G proteins have been determined by cryo-EM in the past 5 years. Further advances in cryo-EM have uncovered dynamics of these receptors, ligands, and signaling partners. Here, we examine the recent structural underpinnings of the class B1 GPCRs with an emphasis on structure–function relationships.
Clinical practice guidelines and real-life practice in hepatocellular carcinoma: A Chinese perspective
Authors: Diyang Xie, Jieyi Shi, Jian Zhou, Jia Fan, Qiang Gao
Journal: Clinical and Molecular Hepatology (2022)

Liver cancer is the fourth most prevalent and the second most lethal cancer in China. Hepatitis B virus (HBV) infection represents a major risk factor for hepatocellular carcinoma (HCC). Liver ultrasonography plus alpha-fetoprotein every 6 months continues to be the predominant surveillance modality. The age-Male-ALBI-Platelets score was recommended in the recent 2022 Chinese guidelines to predict HCC occurrence. The Chinese liver cancer (CNLC) staging system proposed in the 2017 guidelines continues to be the standard model for staging with modifications in the treatment allocations. Considering the aggressive nature of HBV-associated HCC, multimodal and high-intensity strategies like the addition of immunotherapy-based systemic treatment to local therapies, including resection, ablation, and intra-arterial therapies, have been adopted in real-life practices in China. The latest Chinese guidelines recommend atezolizumab plus bevacizumab, suntilimab plus a bevacizumab analog, lenvatinib, sorafenib, donafenib, and FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy as first-line treatment without priority. Regorafenib, apatinib, camrelizumab, and tislelizumab have been added as second-line systemic therapies for patients who progressed on sorafenib. Systemic therapies adopted in real-life practice are sophisticated with various combination modalities and different sequences.
Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: biological insights and clinical advances
Authors: Christopher R. Reilly, Akiko Shimamura
Journal: Blood (2022)

Abstract Shwachman-Diamond syndrome (SDS) is an inherited multisystem ribosomopathy characterized by exocrine pancreatic deficiency, bone marrow failure, and predisposition to myeloid malignancies. The pathobiology of SDS results from impaired ribosomal maturation due to the deficiency of SBDS and the inability to evict the antiassociation factor eIF6 from the 60S ribosomal subunit. Clinical outcomes for patients with SDS who develop myeloid malignancies are extremely poor because of high treatment-related toxicities and a high rate of refractory disease/relapse even after allogeneic hematopoietic stem cell transplant (HSCT). Registry data indicate that outcomes are improved for patients with SDS who undergo routine bone marrow surveillance and receive an HSCT before developing an overt malignancy. However, the optimal approach to hematologic surveillance and the timing of HSCT for patients with SDS is not clearly established. Recent studies have elucidated distinct patterns of somatic blood mutations in patients with SDS that either alleviate the ribosome defect via somatic rescue (heterozygous EIF6 inactivation) or disrupt cellular checkpoints, resulting in increased leukemogenic potential (heterozygous TP53 inactivation). Genomic analysis revealed that most myeloid malignancies in patients with SDS have biallelic loss-of-function TP53 mutations. Single-cell DNA sequencing of SDS bone marrow samples can detect premalignant biallelic TP53-mutated clones before clinical diagnosis, suggesting that molecular surveillance may enhance the detection of incipient myeloid malignancies when HSCT may be most effective. Here, we review the clinical, genetic, and biologic features of SDS. In addition, we present evidence supporting the hematologic surveillance for patients with SDS that incorporates clinical, pathologic, and molecular data to risk stratify patients and prioritize transplant evaluation for patients with SDS with high-risk features.
Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity
Authors: Paolo D. A. Vignali, Kristin DePeaux, McLane J. Watson, Chenxian Ye, B. Rhodes Ford, Konstantinos Lontos, Nicole K. McGaa, Nicole E. Scharping, Ashley V. Menk, Simon C. Robson, Amanda C. Poholek, Dayana B. Rivadeneira, Greg M. Delgoffe
Journal: Nature Immunology (2022)
Association Between Genetic Risk, Adherence to Healthy Lifestyle Behavior, and Thyroid Cancer Risk
Authors: Xiuming Feng, Fei Wang, Wenjun Yang, Yuan Zheng, Chaoqun Liu, Lulu Huang, Longman Li, Hong Cheng, Haiqing Cai, Xiangzhi Li, Xing Chen, Xiaobo Yang
Journal: JAMA Network Open (2022)

Importance Genetic and lifestyle factors are related to thyroid cancer (TC). Whether a healthy lifestyle is associated with TC and could attenuate the influence of genetic variants in TC remains equivocal. Objectives To examine the associations between genetics and healthy lifestyle with incident TC and whether adherence to a healthy lifestyle modifies the association between genetic variants and TC. Design, Setting, and Participants A prospective cohort study using UK Biobank data recruited 502 505 participants aged 40 to 69 years between March 13, 2006, and October 1, 2010. A total of 307 803 participants of European descent were recruited at baseline, and 264 956 participants were available for the present study. Data analysis was conducted from November 1, 2021, to April 22, 2022. Exposures Lifestyle behaviors were determined by diet index, physical activity, weight, smoking, and alcohol consumption. Lifestyle was categorized as unfavorable (scores 0-1), intermediate (score 2), and favorable (scores 3-5). The polygenic risk score (PRS) was derived from a meta–genome-wide association study using 3 cohorts and categorized as low, intermediate, and high. Main Outcomes and Measures Thyroid cancer was defined using the International Classification of Diseases, Ninth Revision (code 193), International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (code C73), and self-report (code 1065). Results Of 264 956 participants, 137 665 were women (52%). The median age was 57 (IQR, 49-62) years. During a median follow-up of 11.1 (IQR, 10.33-11.75) years (2 885 046 person-years), 423 incident TCs were ascertained (14.66 per 100 000 person-years). Higher PRSs were associated with TC (hazard ratio [HR], 2.25; 95% CI, 1.91-2.64; P = 8.65 × 10 −23 ). An unfavorable lifestyle was also associated with a higher risk of TC (HR, 1.93; 95% CI, 1.50-2.49; P &amp;amp;lt; .001). When stratified by PRS, unfavorable lifestyle was associated with TC in the higher PRS group (favorable vs unfavorable HR, 0.52; 95% CI, 0.37-0.73; P &amp;amp;lt; .001). Furthermore, participants with both a high PRS and unfavorable lifestyle had the highest risk of TC (HR, 4.89; 95% CI, 3.03-7.91; P &amp;amp;lt; .001). Conclusions and Relevance In this prospective cohort study, genetic and lifestyle factors were independently associated with incident TC, which suggests that a healthier lifestyle may attenuate the deleterious influence of genetics on the risk of TC in individuals of European descent.
Complications Following Elective Major Noncardiac Surgery Among Patients With Prior SARS-CoV-2 Infection
Authors: Kieran L. Quinn, Anjie Huang, Chaim M. Bell, Allan S. Detsky, Lauren Lapointe-Shaw, Laura C. Rosella, David R. Urbach, Fahad Razak, Amol A. Verma
Journal: JAMA Network Open (2022)

Importance There is an urgent need for evidence to inform preoperative risk assessment for the millions of people who have had SARS-CoV-2 infection and are awaiting elective surgery, which is critical to surgical care planning and informed consent. Objective To assess the association of prior SARS-CoV-2 infection with death, major adverse cardiovascular events, and rehospitalization after elective major noncardiac surgery. Design, Setting, and Participants This population-based cohort study included adults who had received a polymerase chain reaction test for SARS-CoV-2 infection within 6 months prior to elective major noncardiac surgery in Ontario, Canada, between April 2020 and October 2021, with 30 days follow-up. Exposures Positive SARS-CoV-2 polymerase chain reaction test result. Main Outcomes and Measures The main outcome was the composite of death, major adverse cardiovascular events, and all-cause rehospitalization within 30 days after surgery. Results Of 71 144 patients who underwent elective major noncardiac surgery (median age, 66 years [IQR, 57-73 years]; 59.8% female), 960 had prior SARS-CoV-2 infection (1.3%) and 70 184 had negative test results (98.7%). Prior infection was not associated with the composite risk of death, major adverse cardiovascular events, and rehospitalization within 30 days of elective major noncardiac surgery (5.3% absolute event rate [n = 3770]; 960 patients with a positive test result; adjusted relative risk [aRR], 0.91; 95% CI, 0.68-1.21). There was also no association between prior infection with SARS-CoV-2 and postoperative outcomes when the time between infection and surgery was less than 4 weeks (aRR, 1.15; 95% CI, 0.64-2.09) or less than 7 weeks (aRR, 0.95; 95% CI, 0.56-1.61) and among those who were previously vaccinated (aRR, 0.81; 95% CI, 0.52-1.26). Conclusions and Relevance In this study, prior infection with SARS-CoV-2 was not associated with death, major adverse cardiovascular events, or rehospitalization following elective major noncardiac surgery, although low event rates and wide 95% CIs do not preclude a potentially meaningful increase in overall risk.
Comparison of Care Quality Metrics in 2-Sided Risk Medicare Advantage vs Fee-for-Service Medicare Programs
Authors: Kenneth Cohen, Omid Ameli, Christine E. Chaisson, Kierstin Catlett, Jonathan Chiang, Amy Kwong, Samira Kamrudin, Boris Vabson
Journal: JAMA Network Open (2022)

Medicare Advantage is associated with improved health outcomes, increased care efficiency, and lower out-of-pocket costs compared with fee-for-service (FFS) Medicare. When engaged in 2-sided risk arrangements, physicians are incented to offer high value for patients; however, no studies have explored the quality and efficiency outcomes in 2-sided risk Medicare Advantage models compared with FFS Medicare.To compare quality and efficiency of care between physicians using a Medicare Advantage 2-sided risk model and FFS Medicare.This retrospective cohort analysis with exact and propensity score-matched design used claims data from January 1, 2018, to December 31, 2019. Participants included beneficiaries enrolled in a Medicare Advantage 2-sided risk model (ie, physicians assumed the financial risk of total costs of care) and those in an FFS Medicare program in a 5% limited data set with part A and B coverage residing in 6 states (Arizona, California, Florida, Nevada, Texas, and Utah). Data were analyzed from February 1 to June 15, 2022.Medicare Advantage 2-sided risk model seen in practices that are part of a nationwide health care delivery organization compared with traditional FFS Medicare.Comparative analysis of 8 quality and efficiency metrics in populations enrolled in a 2-sided risk-model Medicare Advantage program and 5% FFS Medicare.In this analytic cohort of 316 312 individuals (158 156 in each group), 46.11% were men and 53.89% were women; 32.72% were aged 65-69 years, 29.44% were aged 70-74 years, 19.05% were aged 75-79 years, 10.84% were aged 80-85 years, and 7.95% were 85 years or older. The Medicare Advantage model was associated with care of higher quality and efficiency in all 8 metrics compared with the FFS model. This included lower odds of inpatient admission (-18%; odds ratio [OR], 0.82 [95% CI, 0.79-0.84]), inpatient admission through the emergency department (ED) (-6%; OR, 0.94 [95% CI, 0.91-0.97]), ED visits (-11%; OR, 0.89 [95% CI, 0.86-0.91]), avoidable ED visits (-14%; OR, 0.86 [95% CI, 0.82-0.89]), 30-day inpatient readmission (-9%; rate ratio, 0.91 [95% CI, 0.86-0.98]), admission for stroke or myocardial infarction (-10%; OR, 0.90 [95% CI, 0.83-0.98]), and hospitalization for chronic obstructive pulmonary disease or asthma exacerbation (-44%; OR, 0.56 [95% CI, 0.50-0.62]).The improvements observed in this study may be partly or fully attributed to the Medicare Advantage model. The Medicare Advantage risk adjustment system appears to be meeting its intended goal by aligning the capitation payments to the health care burden of the individual beneficiary and aggregate population served, thus providing revenue to develop infrastructure that supports improvements in quality and efficiency for the patients enrolled in Medicare Advantage models with 2-sided risk.
Neutralization against BA.2.75.2, BQ.1.1, and XBB from mRNA Bivalent Booster
Authors: Meredith E Davis-Gardner, Lilin Lai, Bushra Wali, Hady Samaha, Daniel Solis, Matthew Lee, Andrea Porter-Morrison, Ian T Hentenaar, Fumiko Yamamoto, Sucheta Godbole, Yuan Liu, Daniel C Douek, Frances Eun-Hyung Lee, Nadine Rouphael, Alberto Moreno, Benjamin A Pinsky, Mehul S Suthar
Journal: New England Journal of Medicine (2022)
The Construction of Alkaline Phosphatase‐Responsive Biomaterial and Its Application for In Vivo Urinary Tract Infection Therapy
Authors: Jing Zhang, Ying Fu, Rongtao Zhou, Moli Yin, Wenhe Zhu, Shunjie Yan, Huiyan Wang
Journal: Advanced Healthcare Materials (2022)

Abstract Urinary tract infections caused by urinary catheter implantations are becoming more serious. Therefore, the construction of a responsive antibacterial biomaterial that can not only provide biocompatible conditions, but also effectively prevent the growth and metabolism of bacteria, is urgently needed. In this work, a benzophenone‐derived phosphatase light‐triggered antibacterial agent is designed and synthesized, which is tethered to the biological materials using a one‐step method for in vivo antibacterial therapy. This surface could kill gram‐positive bacteria ( Staphylococcus aureus ) and gram‐negative bacteria ( Escherichia coli ). More importantly, because this material exhibited a zwitterion structure, it does not damage blood cells and tissue cells. When the bacteria interact with this surface, the initial fouling of the bacteria is reduced by zwitterion hydration. When the bacteria actively accumulate and metabolize to produce a certain amount of alkaline phosphatase, the surface immediately started the sterilization performance, and the bactericidal effect is achieved by destroying the bacterial cell membrane. In summary, an antibacterial biomaterial that shows biocompatibility with mammalian cells is successfully constructed, providing new ideas for the development of intelligent urinary catheters.
Potent high-avidity neutralizing antibodies and T cell responses after COVID-19 vaccination in individuals with B cell lymphoma and multiple myeloma
Authors: Andrea Keppler-Hafkemeyer, Christine Greil, Paul R. Wratil, Khalid Shoumariyeh, Marcel Stern, Annika Hafkemeyer, Driti Ashok, Alexandra Hollaus, Gaia Lupoli, Alina Priller, Marie L. Bischof, Gabriele Ihorst, Monika Engelhardt, Reinhard Marks, Jürgen Finke, Hannah Bertrand, Christopher Dächert, Maximilian Muenchhoff, Irina Badell, Florian Emmerich, Hridi Halder, Patricia M. Spaeth, Percy A. Knolle, Ulrike Protzer, Michael von Bergwelt-Baildon, Justus Duyster, Tanja N. Hartmann, Andreas Moosmann, Oliver T. Keppler
Journal: Nature Cancer (2022)

Abstract Individuals with hematologic malignancies are at increased risk for severe coronavirus disease 2019 (COVID-19), yet profound analyses of COVID-19 vaccine-induced immunity are scarce. Here we present an observational study with expanded methodological analysis of a longitudinal, primarily BNT162b2 mRNA-vaccinated cohort of 60 infection-naive individuals with B cell lymphomas and multiple myeloma. We show that many of these individuals, despite markedly lower anti-spike IgG titers, rapidly develop potent infection neutralization capacities against several severe acute respiratory syndrome coronavirus 2 variants of concern (VoCs). The observed increased neutralization capacity per anti-spike antibody unit was paralleled by an early step increase in antibody avidity between the second and third vaccination. All individuals with hematologic malignancies, including those depleted of B cells and individuals with multiple myeloma, exhibited a robust T cell response to peptides derived from the spike protein of VoCs Delta and Omicron (BA.1). Consistently, breakthrough infections were mainly of mild to moderate severity. We conclude that COVID-19 vaccination can induce broad antiviral immunity including ultrapotent neutralizing antibodies with high avidity in different hematologic malignancies.
Rebalancing TGFβ1/BMP signals in exhausted T cells unlocks responsiveness to immune checkpoint blockade therapy
Authors: Abbey A. Saadey, Amir Yousif, Nicole Osborne, Roya Shahinfar, Yu-Lin Chen, Brooke Laster, Meera Rajeev, Parker Bauman, Amy Webb, Hazem E. Ghoneim
Journal: Nature Immunology (2022)
Peptide Vaccine Against ADAMTS-7 Ameliorates Atherosclerosis and Postinjury Neointima Hyperplasia
Authors: Zihan Ma, Chenfeng Mao, Xiao Chen, Shiyu Yang, Zhihua Qiu, Baoqi Yu, Yiting Jia, Chao Wu, Yiyi Wang, Yuhui Wang, Rui Gu, Fang Yu, Yanhui Yin, Xian Wang, Qingbo Xu, Chuanju Liu, Yuhua Liao, Jingang Zheng, Yi Fu, Wei Kong
Journal: Circulation (2022)

Background: The metalloprotease ADAMTS-7 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 7) is a novel locus associated with human coronary atherosclerosis. ADAMTS-7 deletion protects against atherosclerosis and vascular restenosis in rodents. Methods: We designed 3 potential vaccines consisting of distinct B cell epitopic peptides derived from ADAMTS-7 and conjugated with the carrier protein KLH (keyhole limpet hemocyanin) as well as aluminum hydroxide as an adjuvant. Arterial ligation or wire injury was used to induce neointima in mice, whereas ApoE -/- and LDLR -/- (LDLR [low-density lipoprotein receptor]) mice fed a high-fat diet were applied to assess atherosclerosis. In addition, coronary stent implantation was performed on vaccine-immunized Bama miniature pigs, followed by optical coherence tomography to evaluate coronary intimal hyperplasia. Results: A vaccine, ATS7vac, was screened out from 3 candidates to effectively inhibit intimal thickening in murine carotid artery ligation models after vaccination. As well, immunization with ATS7vac alleviated neointima formation in murine wire injury models and mitigated atherosclerotic lesions in both hyperlipidemic ApoE -/- and LDLR -/- mice without lowering lipid levels. Preclinically, ATS7vac markedly impeded intimal hyperplasia in swine stented coronary arteries, but without significant immune-related organ injuries. Mechanistically, ATS7vac vaccination produced specific antibodies against ADAMTS-7, which markedly repressed ADAMTS-7–mediated COMP (cartilage oligomeric matrix protein) and TSP-1 (thrombospondin-1) degradation and subsequently inhibited vascular smooth muscle cell migration but promoted re-endothelialization. Conclusions: ATS7vac is a novel atherosclerosis vaccine that also alleviates in-stent restenosis. The application of ATS7vac would be a complementary therapeutic avenue to the current lipid-lowering strategy for atherosclerotic disease.
NDRG1 Signaling Is Essential for Endothelial Inflammation and Vascular Remodeling
Authors: Guanxin Zhang, Qing Qin, Chen Zhang, Xiaobo Sun, Kyosuke Kazama, Bing Yi, Fang Cheng, Zhi-Fu Guo, Jianxin Sun
Journal: Circulation Research (2022)

NDRG-1 (N-myc downstream-regulated gene 1) is a member of NDRG family that plays essential roles in cell differentiation, proliferation, and stress responses. Although the expression of NDRG1 is regulated by fluid shear stress, its roles in vascular biology remain poorly understood. The purpose of the study is to determine the functional significance of NDRG1 in vascular inflammation and remodeling. By using quantitative polymerase chain reaction, western blot, and immunohistochemistry, we demonstrate that the expression of NDRG1 is markedly increased in cytokine-stimulated endothelial cells and in human and mouse atherosclerotic lesions. To determine the role of NDRG1 in endothelial activation, we performed loss-of-function studies using NDRG1 short hairpin RNA. Our results demonstrate that NDRG1 knockdown by lentivirus bearing NDRG1 short hairpin RNA substantially attenuates both IL-1β (interleukin-1β) and TNF-α (tumor necrosis factor-α)-induced expression of cytokines/chemokines and adhesion molecules. Intriguingly, inhibition of NDRG1 also significantly attenuates the expression of procoagulant molecules, such as PAI-1 (plasminogen activator inhibitor type 1) and TF (tissue factor), and increases the expression of TM (thrombomodulin) and t-PA (tissue-type plasminogen activator), thus exerting potent antithrombotic effects in endothelial cells. Mechanistically, we showed that NDRG1 interacts with orphan Nur77 (nuclear receptor) and functionally inhibits the transcriptional activity of Nur77 and NF-κB (nuclear factor Kappa B) in endothelial cells. Moreover, in NDRG1 knockdown cells, both cytokine-induced mitogen-activated protein kinase activation, c-Jun phosphorylation, and AP-1 (activator protein 1) transcriptional activity are substantially inhibited. Neointima and atherosclerosis formation induced by carotid artery ligation and arterial thrombosis were markedly attenuated in endothelial cell-specific NDRG1 knockout mice compared with their wild-type littermates. Our results for the first time identify NDRG1 as a critical mediator implicated in regulating endothelial inflammation, thrombotic responses, and vascular remodeling, and suggest that inhibition of NDRG1 may represent a novel therapeutic strategy for inflammatory vascular diseases, such as atherothrombosis and restenosis.
Targeted long-read sequencing facilitates phased diploid assembly and genotyping of the human T cell receptor alpha, delta, and beta loci
Authors: Oscar L. Rodriguez, Catherine A. Silver, Kaitlyn Shields, Melissa L. Smith, Corey T. Watson
Journal: Cell Genomics (2022)

T cell receptors (TCRs) recognize peptide fragments presented by the major histocompatibility complex (MHC) and are critical to T cell-mediated immunity. Recent data have indicated that genetic diversity within TCR-encoding gene regions is underexplored, limiting understanding of the impact of TCR loci polymorphisms on TCR function in disease, even though TCR repertoire signatures (1) are heritable and (2) associate with disease phenotypes. To address this, we developed a targeted long-read sequencing approach to generate highly accurate haplotype resolved assemblies of the TCR beta (TRB) and alpha/delta (TRA/D) loci, facilitating the genotyping of all variant types, including structural variants. We validate our approach using two mother-father-child trios and 5 unrelated donors representing multiple populations. This resulted in improved genotyping accuracy and the discovery of 84 undocumented V, D, J, and C alleles, demonstrating the utility of this framework for improving our understanding of TCR diversity and function in disease.